Every week this new series will uncover an unreported clinical trial

Nick DeVito and Ben Goldacre

Background

The US FDA Amendments Act (FDAAA 2007) requires certain clinical trials to report their results onto ClinicalTrials.gov within one year of completion. Our FDAAA TrialsTracker shows all individual trials that breach this legal requirement. Once a week, we write about one unreported clinical trial: you can read more background here.

Trial NCT00515281

The week’s unreported trial is “Inhaled Nitric Oxide and Neuroprotection in Premature Infants” (NCT00515281). This study had an estimated enrollment of 484 premature infants (birthweight ≤ 1500g, < 31 weeks gestation) requiring respiratory support at the University of Chicago’s medical centre. The intervention group received inhaled nitric oxide, combined with oxygen or room air until 33 weeks corrected age; the control group received 7 days of inhaled nitric oxide followed by O2 or room air treatment as clinically appropriate until 33 weeks corrected age. The primary outcomes were: neurodevelopment measured over two years (with no precise measure indicated); and the presence of bronchopulmonary dysplasia, a chronic lung disease in infants, at 36 weeks corrected age. The secondary outcomes were severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL), two characteristics of brain damage in infants. The study was blinded for all participants and study personnel.

Clinical discussion

This is an important trial that could impact the vital treatment decisions made to treat premature infants around the world. There is some doubt about the effectiveness of inhaled nitric oxide in preterm infants; however this study was based on promising preliminary findings by the study PI and colleagues. The neurodevelopmental issues associated with preterm birth are serious and potentially long-lasting. An estimated 14.9 million babies (11.1% of all births) worldwide were born prematurely in 2010. The premature birth rate is estimated at 8.6% across developed countries, and 12% in the US. A 2014 review notes that major neurodevelopmental disabilities are “2 to 3 times more likely to occur in low birth weight infants compared to normal weight infants, and its prevalence increases with more prematurity and lower weight at birth.” Having complete data on strategies to minimise the impact of premature birth on neurological development is an important area of research.

Legislative discussion

We intend that this series should occasionally shed light on interesting issues around transparency rules, and how registry data is used. You can read some general background about the FDA Amendments Act 2007—and why a trial is considered “due”—here and here.

This trial presents an interesting talking case for the legislation. Legally, this trial is overdue to report its results, because the estimated completion date provided by the sponsor is over a year in the past. Some reading the registry entry may take issue with that: because this trial’s registry entry has not been updated since May 2016, two years ago. However, ClinicalTrials.gov requires estimated and actual completion dates to be updated within 30 days of any changes to the date provided; and in the absence of an “actual” completion date, the law itself (FDAAA 2007, 402(j)(3)(E)(i)) specifically requires results to be reported within 1 year of the “estimated” primary completion date. It seems likely that those drafting the law wanted sponsors to be motivated to maintain good current data on their registry entry; and wanted to avoid a situation where trialists might avoid their reporting responsibilities by leaving their registry data out of date.

Similarly, the study’s “status” is listed as “Unknown” due to the two year lapse in updating the record, rather than “completed.” It was previously “Active, not recruiting”: however the recruitment status is not considered when determining the responsibility to report under FDAAA (unless the trial is “Withdrawn”, meaning it did not enroll any participants). Again, it seems likely that the law was intended to use the “sting” of being denoted as legally overdue to incentivise trialists to keep their registry data accurate.

This trial therefore illustrates an important issue. The law is clear: a poorly maintained registry entry does not protect sponsors from their legal obligation to report trial results under the FDAAA. Sponsors are subject to fines from the FDA of up to $11,651 a day for each trial counted as overdue under FDAAA. The law requires sponsors to keep their registry entries current and accurate, because inaccurate registry data from sponsors can prevent scrutiny of trial reporting. We will discuss further legislative issues as this series develops.

Conclusion

The non-reporting of this study’s results, along with a failure to properly maintain the registry entry, are both concerning. This unreported trial was sponsored by the University of Chicago. The PI is Dr. Michael D. Schreiber. We hope the investigators will share the results of this trial soon.

Ben Goldacre is a doctor, author, and director of the EBM DataLab at the University of Oxford. He co-founded the AllTrials campaign for trials transparency.

Competing interests: BG has received research funding from the Laura and John Arnold Foundation, the Wellcome Trust, the Oxford Biomedical Research Centre, the NHS National Institute for Health Research School of Primary Care Research, the Health Foundation, and the World Health Organization; he also receives personal income from speaking and writing for lay audiences on the misuse of science.

Nicholas J DeVito is a researcher at the EBM Datalab at the University of Oxford.

Competing interests: ND is employed on BG’s LJAF grant.